primary and secondary prevention of cardiovascular disease in patients with hyperlipoproteinemia a

DOI 10.1007/s11789-017-0090-3Primary and secondary prevention of cardiovascular disease in patients with hyperlipoproteinemia a P.. Abstract General lipoprotein Lp a screening can help t

DOI 10.1007/s11789-017-0090-3

Primary and secondary prevention of cardiovascular disease in

patients with hyperlipoproteinemia (a)

P Grützmacher 1 · B Öhm 1 · S Szymczak 1 · C Dorbath 1 · M Brzoska 1 · C Kleinert 1

© The Author(s) 2017 This article is available at SpringerLink with Open Access.

Abstract General lipoprotein (Lp) (a) screening can help

to identify patients at high risk for cardiovascular disease

Non-invasive methods allow early detection of clinically

asymptomatic incipient atherosclerotic disease Medical

treatment options are still unsatisfactory Lp(a) apheresis

is an established treatment in Germany for secondary

pre-vention of progressive cardiovascular disease Statin-based

lowering of LDL cholesterol and thrombocyte aggregation

inhibitors still represent the basis of medical treatment

Target levels for LDL-cholesterol should be modified in

patients with hyperlipoproteinemia (a)

Keywords Lipoprotein (a) · Lp (a) apheresis ·

Cardiovascular prevention · Target LDL cholesterol

Introduction

The role of Lp (a) as an independent risk factor is

mean-while generally accepted [1 3] The aim of secondary

pre-vention of cardiovascular and other vascular diseases in

patients with hyperlipoproteinemia (a) is to prevent further

lethal and non-lethal complications, if an atherosclerotic

disease is already clinically manifest Mostly the coronary

arteries, the arteries of the lower extremities and the

cere-brovascular system of patients in the second half of life are

This article is part of the special issue “Lp(a) – the underestimated

cardiovascular risk factor”

 P Grützmacher

peter.gruetzmacher@fdk.info

1 2nd Medical Clinic – Nephrology, Hypertension and Vascular

Diseases, AGAPLESION Markus-Hospital, Frankfurt/Main,

Germany

involved Primary prevention usually focuses on younger patients without clinically symptomatic atherosclerotic dis-ease Statins have shown to be effective in primary preven-tion even in patients with intermediate risk [4,5]

The use of non-invasive diagnostic procedures as e g B-mode sonography of blood vessels or cardiac computed tomography contributes to early risk stratification With these techniques a continuous progression of atherosclerotic plaques sometimes can be observed over decades in clin-ically asymptomatic patients Therefore primary and sec-ondary prevention are no longer strictly discriminated

Indication for screening of Lp (a)

As screening for lipoprotein (Lp) (a) of the general pop-ulation is currently not yet recommended, many patients miss early preventive strategies For secondary prevention,

Lp (a) should be measured in premature cardiovascular dis-ease and progressive atherosclerotic disdis-ease despite correc-tion of all other risk factors, especially despite optimal lipid-lowering treatment For primary prevention, Lp (a) screen-ing is recommended in patients with a positive family his-tory of premature cardiovascular diseases, elevated Lp (a) in other family members, familial hypercholesterolemia, and

in high-risk patients with a 10-year risk of fatal cardiovas-cular disease of 5–10% according to the ESC score [6]

It should be discussed to extend Lp (a) screening to ev-ery individual with a vascular event, which can not suffi-ciently be explained by typical risk factors, independent of the patient’s age Furthermore, a high coincidence with ge-netically induced hemostatic defects has to be considered [7]

Table 1 Drugs with significant effects on serum Lp(a) concentration

Evolocumab

Alirocumab

Mipomersen Apo B100 antisense

oligonu-cleotide

ISIS-APO (a) 144367 Apo (a) antisense

oilgo-nucelotide

30–80 Clinical trials still running

No drug has yet been approved for specific treatment of hyperlipoproteinemia (a)

No effect on clinical endpoints has yet been demonstrated in neither drug

Table 2 Primary and secondary prevention of cardiovascular disease in patients with hyperlipoproteinemia (a) Possible therapeutic strategies

Age years

Lifestyle changes

Target LDL-chol

Statins Platelet

inhibition (aspirine)

Additional options

Primary

prevention

Secondary

Prevention

inhibi-tion, anticoagulation as last option?

End-stage renal disease and the nephrotic syndrome are

most frequent causes of secondary hypolipoproteinemia (a)

[8,9]

In many patients, an unexpected cardiovascular event

induces the first measurement of Lp (a) and a profound

evaluation of conventional, generally accepted risk factors;

the German lipid league proposes a general screening of

the whole population by at least one single measurement in

life As the laboratory methods still have a high variance,

2–3 controls may be indicated, if exact risk estimation is

necessary [9,10]

Therapeutic options in hyperlipoproteinemia (a)

Lifestyle changes and statins have no relevant effects on

serum Lp (a) concentrations Several drugs are able to

re-duce elevated Lp (a) levels by 5–30% However, up to now

there is no evidence of any reduction of clinical vascular

endpoints for all substances Neither has any of these drugs

been approved by the German authorities for the treatment

of hyperlipoproteinemia (a) (Table1)

Nicotinic acid at a daily dose of 2–3 g/die can reduce

Lp (a) levels by up to 30% Similar results have been shown

for microsomal triglyceride transfer protein inhibitor

lomi-tapide and the apo-B-100 antisense oligonucleotide

mipom-ersen However, both drugs bear a considerable risk of the development of fatty liver disease, being the main reason of failing German drug approval for the treatment of elevated LDL-cholesterol and lipoprotein (a) levels [11–13] Two PCSK9-antibodies have been introduced for the treatment of severe hypercholesterolemia, refractory to con-ventional drug combinations In contrast to their impressive potential on LDL-cholesterol, the influence on Lp (a) is markedly lower; a lowering of Lp (a) levels by up to 30% has been reported, the reduction rate is below 20% in pa-tients with high levels of Lp (a) [14,15]

A most promising approach is the antisense oligonu-cleotide against apolipoprotein (a), where reduction rates

up to 80% seem possible; nevertheless, the necessary clin-ical study protocols for drug approval have not yet been completed [16] Therefore, in daily practice no option for

a direct medical correction of hyperlipoproteinemia (a) is available

In Germany Lp (a) apheresis is an established treatment for patients with elevated Lp (a) levels providing reduction rates of 60–70% compared to baseline and pre-apheresis levels Lp (a) apheresis has been approved for secondary prevention in patients with clinically manifest cardiovascu-lar diseases, which is progressive despite the correction of all other risk factors, and in patients with already extended

cardiovascular diseases, in whom a progression is assumed

to have deleterious consequences [17]

An impressive reduction of cardiovascular complications

has been observed in five observation studies in different

German patient cohorts [18–23]

The annual quality report of the Kassenärztliche

Bun-desvereinigung of 2015 included 953 patients with isolated

hyperlipoproteinemia (a) treated with regular Lp (a)

aphere-sis [24]

Treatment of hyperlipoproteinemia (a) by

individual risk stratification

Without any effective medical treatment option for

lower-ing Lp(a)-levels, primary prevention has to focus on on the

reduction of the total individual risk for cardiovascular

dis-ease and thus on the correction of classical concomitant risk

factors which are not discussed here (Table2)

In young and healthy patients without risk factors, even

strongly elevated Lp (a) levels to more than 3.5fold above

normal induce only a small increment of the absolute

car-diovascular risk – in spite of doubling the relative risk

However, if other factors such ass smoking, hypertension,

male sex, age >60 years or classical Framingham risks of

>20%/10 years are present, a dramatic increment of the

absolute risk can been observed [25,26]

But the risk of elevated Lp (a) level alone is already

comparable to the risk of smoking or arterial hypertension

in low risk situations, those being classical targets of

pre-ventive efforts in daily practice

Further discrimination of cardiovascular risk is

par-tially possible by the measurement of the genetic variants

rs10455872 and 3798220, which determine the serum

con-centration of Lp (a) as well as the size of Lp (a) particles

by the numbers of kringle IV-type 2 copies [27]

Except for apheresis, specific recommendations for the

management of patients with hyperlipoproteinemia (a) have

not yet been established This is explained by the lack of

therapeutics options and of clinical evidence of any

differ-entiated medical strategy

It has been shown that the cardiovascular risk of

ele-vated of LDL cholesterol is considerably increased in the

presence of an additionally elevated Lp(a) level (a) [28,29]

It is the current concept to establish optimal

LDL-choles-terol target levels in patients with hyperlipoproteinemia (a)

by means of dietary restrictions and the use of statins,

al-though this strategy has not yet been confirmed by clinical

endpoint studies [30]

In patients with moderate risk (score risk 1Ä 5%), the

current ESC/EAS-guideline of 2016 recommend a target

LDL-cholesterol of <115 mg% (<3.0 mmol/l) if at least one

classical major risk factor is present (6) Although Lp(a)

is not yet accepted as a major risk factor, this target level should be implemented for patients with elevated Lp(a)-levels

In patient with a 10-year risk of 5 Ä 10%, ESC/EAS-guidelines recommend a LDL target level of <100 mg%, if

at least one further major risk factor is present It should

be remembered that the risk difference of these 2 groups is mainly caused by gender and age

The use of platelet inhibition is not generally recom-mended for primary prevention even in elderly persons [40]

As Lp (a) exerts considerable prothrombotic effects [31,

32], a primary protection can be discussed, e g using low dose aspirin in adult patients >35 years of age At least

in patients >60 years, a positive risk/benefit ratio may be expected, if already minor evidence of vessel alterations is present

In patients with clinically symptomatic atherosclerotic disease, secondary prevention regularly includes the use of platelet inhibitors, usually aspirin at a dose of 100 mg/die and the use of statins in order to reduce LDL-cholesterol below a target level of 70 mg% [33–36]

In Lp(a) patients with premature cardiovascular disease below 60 years of age, a therapeutic target of <50 mg% may

be regarded as a more safe strategy, and in patients with advanced or progressive cardiovascular disease despite op-timal guideline-based therapy, aggressive lowering of LDL-cholesterol to <30 mg% as well as combined platelet inhi-bition should be considered, as these regimens hardly bear any clinically relevant risk [37,38]

Apart from that, the correction of elevated serum triglyc-erides should further contribute to a reduction of the total cardiovascular risk [39]

In exceptional cases with advanced and recurrent vas-cular occlusions, triple therapy including anticoagulatory substances as vitamin K antagonists, thrombin and factor

Xa inhibitors may be advantageous [38,40]

Conclusion

In patients with hyperlipidaemia (a) very early identifica-tion and comprehensive risk management are mandatory for successful cardiovascular prevention as long as a direct and efficient medical correction is not available and Lp(a) apheresis is not yet required

Conflict of interest P Grützmacher has received honoraria for lectures

from Fresenius, B Braun, Diamed, Kaneka, Amgen, Sanofi and MSD,

B Öhm, S Szymczak, C Dorbath, M Brzoska and C Kleinert declare that they have no competing interests.

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http:// creativecommons.org/licenses/by/4.0/ ), which permits unrestricted use, distribution, and reproduction in any medium, provided you give

appropriate credit to the original author(s) and the source, provide a

link to the Creative Commons license, and indicate if changes were

made.

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